Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease.

It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-α gene affect the risk of developing Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-α gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-α polymorphisms (−850, −308, −863, −238, and −1031) and AD were retrieved and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested a significant association between −850 polymorphism and AD risk (TT vs. TC+CC: pooled odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08–2.29; p=0.02) with no evidence of between-study heterogeneity (χ2, p>0.1). Subgroup analysis suggested that the possession of T allele significantly increased the risk of AD associated with carriage of the apolipoprotein E ɛ4 allele in Caucasian Australians and Northern Europeans (TT+TC vs. CC: OR, 1.95; 95% CI, 1.45–2.62; p=0.00001; p>0.1; χ2 for heterogeneity, p>0.1). No significant difference in genotype distribution of −308 polymorphism in AD was found, with a high degree of between-study heterogeneity. For the −863 and −1031 polymorphisms we did not find an association with AD, but significant between-study heterogeneity discouraged genotype data pooling. Only four studies investigated the −238 variant and the results were not significant. Current findings support an association between −850 C>T polymorphism and the risk of developing AD; hence, they strengthen the suggestion of a potential role for anti-TNF therapy to maintain physiologic levels of TNF-α.